The objective of this proposal is to examine the role of interactions between stromal and epithelial cells in the regulation of breast cancer growth. The fundamental hypothesis of this study is that breast tumor stroma is an essential and active participant in the process of malignant tumor progression. While the coordinated growth of stromal and epithelial elements is necessary for tumor survival, the specifics of the growth enhancing interactions between these cell types is not clearly defined. The preliminary data discussed below suggest that the insulin-like growth factors, IGF-I and IGF-II, may play an important role in the these interactions. Specifically, breast fibroblasts from benign lesions express IGF-I, while most fibroblasts from breast cancers express IGF-II. Since the insulin-like growth factors are potent mitogens for breast tumor epithelial cells, this further supports the notion of a paracrine growth promoting role for the insulin-like growth factors in breast lesions, and suggests that IGF-II may be the more important growth promoter in malignant lesions. We have developed two model systems which enable us to qualitatively and quantitatively study the growth promoting paracrine interactions between breast fibroblasts and breast tumor epithelial cells. Using these model systems, we will characterize paracrine interactions between breast epithelial cells and breast fibroblasts from benign and malignant lesions. Further, using antibodies and growth factor antagonists in this model system, we will attempt to interfere with paracrine growth stimulation by inhibition of specific growth factors such as IGF-II. Under the current proposal, we will also examine the expression of IGF-I, IGF-Il and other growth factors in fibroblasts from patients with familial cancer syndromes to determine if expression of a specific growth factor such as IGF-II correlates with risk of malignancy. These studies will provide a better understanding of the growth promoting relationships between breast tumor stromal and epithelial cells and may help to identify new theraputic targets in breast cancer treatment.